S1

A novel Supramolecular
Palladium Catalyst for the
Asymmetric Reduction of
Imines in Aqueous Media
Wender A. da Silva,a,b Manoel T. Rodrigues Jr.,c N. Shankaraiah,a Renan B.
Ferreira,c Carlos Kleber Z. Andrade,b Ronaldo A. Pilli,c* Leonardo S. Santos,a*
a

Laboratory of Asymmetric Synthesis, Chemistry Institute of Natural Resources, Universidad de Talca,

Talca, PO Box 747, Talca, Chile
b
Institute of Chemistry, Universidade de Braslia, UnB, Braslia, Brazil
c
Chemistry Institute, Universidade de Campinas, UNICAMP, Campinas, Brazil
pilli@iqm.unicamp.br; lssantos@utalca.cl

Supporting Information

General Information
Chemicals were used as purchased unless otherwise noticed. Tetrahydrofuran (THF)
was distilled from sodium/benzophenone immediately prior to use. Methanol was
distilled from magnesium and catalytic amount of iodine. Dichloromethane, acetonitrile,
benzene and triethylamine were distilled from calcium hydride immediately prior to use.
Phosphorous oxychloride was distilled immediately prior to use. N,NDimethylformamide (DMF) was distilled from calcium hydride under reduced pressure
below 70 C. The reaction progress was monitored by thin layer chromatography on
silica gel (aluminum foils) and spotted under UV light (254 nm), followed by staining
with ethanolic 25% phosphomolibdic solution or aqueous KMnO4. Purification by
column chromatography was carried out with silica gel (70-230 or 230-400 Mesh).
1
H-NMR spectra were measured at 250 or 300 MHz and the 13C-NMR spectra at 62.5 or
75 MHz, in CDCl3 or CD3OD at room temperature. Chemical shifts () were reported in
ppm and the coupling constants (3J) in Hertz (Hz). Signal multiplicity was assigned as
singlet (s), doublet (d), double doublet (dd), triplet (t), double triplet (dt), quartet (q),
quintuplet (qt), multiplet (m) and broad (br). Infrared spectra were measured as films in
NaCl cell and the wavenumber is expressed in cm1. Melting points are not corrected.

S2
Harmicine.
Methyl
4-{[2-(1H-indol-3-yl)ethyl]amino}-4oxobutanoate (4). To a solution of tryptamine (0.500 g,
HN
O
3.10 mmol) in acetone (10 mL) was added succinic
N
anhydride (0.315 g, 3.10 mmol) dissolved in acetone (5
H
mL). The reaction mixture was stirred 12 h at rt. The
CO2 Me solvent was removed under reduced pressure and
methanol (10 mL) was added, followed by the addition of
thionyl chloride (1.0 mL, 14 mmol) at 0C. The reaction was allowed to reach rt and
stirred 16 h. The solvent was removed under reduced pressure and the crude product
was purified by column chromatography on silica gel (hexane/ethyl acetate 50%).
Methyl ester 4 (780 mg, 2.85 mmols) in 92% yield as a white solid (m.p.: 102-103 C,
lit.1 101-102 C). IR (film): 3340, 2856, 1725, 1652. 1H-NMR (250 MHz, CDCl3) :
2.39 (t, J 6.8 Hz, 2H); 2.64 (t, J 6.9 Hz, 2H); 2.98 (t, J 7.2 Hz, 2H); 3.57 (t, J 7,5 Hz,
2H); 3.65 (s, 3H); 5.30 (br s, 1H); 7,04-7.18 (m, 3H); 7.35 (d, J 7.8 Hz, 1H); 7.58 (d, J
7.8 Hz, 1H); 8.30 (br s, 1H). 13C-RMN (62.5 MHz, CDCl3), : 25.2 (CH2); 29.2 (CH2);
30.9 (CH2); 39.8 (CH2); 51.7 (CH3); 111.2 (CH); 112.7 (C0); 118.6 (CH); 119.3 (CH);
122.0 (CH); 122.1 (CH); 127.2 (C0); 136.3 (C0); 171.3 (C0); 173.4 (C0).
General procedure for -CD mediated reduction of imines. An equimolar amount of
imine (0.5 mmol) was added to a suspension of dried -CD (0.5 mmol) in 2.5 mL of
aqueous sodium bicarbonate solution (0.2 mol/L). The mixture was stirred at room
temperature overnight and the resulting slurry lyophilized to give a cream powder that
was used without further purification. Then, the imine-CD complex was resuspended in
4.0 mL of H2O:CH2Cl2 (1:1), and PdCl2 (0.15 mmol) was added at once followed by
Et3N (0.36 mmol). The temperature was dropped to 0 oC and Et3SiH (2.0 mmol) added
dropwised. The mixture was stirred at 0 C for 2 h. The mixture was basified to pH 9,
extracted with CH2Cl2 and purified by flash chromatography to afford the respective
amines using AcOEt:MeOH:NH4OH (95:5:1) as eluent.

1,2,5,6,11,11b-Hexahydro-indolizino[8,
7-b]indol-3-one
(3f).
An
equimolar
amount
of
imine
1f
(0.5
mmol)
was added
N
O
N
to a suspension of dried -CD (0.5 mmol) in 2.5 mL of
H
aqueous sodium bicarbonate solution (0.2 mol/L). The
mixture was stirred at room temperature overnight and the resulting slurry lyophilized
to give a cream powder that was used without further purification. Then, the imine-CD
complex was resuspended in 4.0 mL of H2O:CH2Cl2 (1:1), and PdCl2 (0.15 mmol) was
added at once followed by Et3N (0.36 mmol). The temperature was dropped to 0 oC and
Et3SiH (2.0 mmol) added dropwised. The mixture was stirred at 0 C for 2 h. The
mixture was acidified with HCl (1.0 mol/L) to pH 3, and stirred for additionally 1 h.
Then the mixture was extracted with CH2Cl2, dried with Na2SO4, and rotaevaporated.
The crude mixture was purified by column chromatography on silica gel
(chloroform/methanol 9:1 v/v) to afford 3f (0.410 mg, 1.60 mmol) in 95% yield as a
brown viscous unstable oil, and 85% ee by HPLC analysis (Welch-01, hexane/2propanol/diethylamine = 80: 20: 0.1, 1.0 mL/min, 254 nm, minor isomer 4.1 min, major
isomer 4.5 min).
m.p.: 250 oC; lit12h: 251-252 C. Specific optical rotation: []20D =
+234 (c=1.0, CHCl3); lit2: []20D = +249,5 (c=1.0, CHCl3). FTIR (film): 3260, 2950,
2847, 1669, 1455, 742. 1H-NMR (250 MHz, CD3OD) : 1.86-2.01 (m, 1H); 2.38-2.48
H

S3
(m, 1H); 2.56-2.68 (m, 2H); 2.75-2.79 (m, 2H); 3.00-3.25 (m, 1H); 4.38-4.46 (m, 1H);
4.96-5.01 (m, 1H); 7.00 (dt, J 1.2 and 7.0 Hz, 1H); 7.08 (dt, J 1.2 and 7.0 Hz, 1H); 7.287.32 (m, 1H); 7.39-7.42 (m, 1H). 13C-RMN (62.5 MHz, CD3OD) : 22.2 (CH2); 27.0
(CH2); 32.7 (CH2); 39.1 (CH2); 56.4 (CH); 107.6 (C0); 112.2 (CH); 119.0 (CH); 120.2
(CH); 122.7 (CH); 128.2 (C0); 135.0 (C0); 138.3 (C0); 176.1 (C0).
(+)-Harmicine (5). A flame dried round-bottomed flask was
charged with AlCl3 (0.05 g, 0.38 mmol) and THF (3.0 mL) under
H
N
nitrogen atmosphere. The mixture was cooled at 0 oC and a 2,4M
N
H
THF soln. of LiAlH4 (0.55 mL, 1.33 mmol) was added. After
stirring 10 min. at 0 oC, a soln. of lactam 3f (0.15 g, 0.66 mmol) in THF (3.0 mL) was
added via canula. The reaction mixture was stirred 30 min. at rt, quenched by the
addition of satd. aq. NH4Cl (0.1 mL) and poured into satd. aq. NaHCO3 (20 mL). After
extraction with ethyl acetate (2X15 mL), the organic phase was washed with brine
(2X15 mL) and dried with MgSO4. The crude product was purified by column
chromatography on silica gel (chloroform/methanol 9:1 v/v) to afford (+)-harmicine 3
(0.126 g, 0.59 mmol) in 90% yield as yellow solid. (m.p. 160-161 oC; lit.3 161-164 C).
Specific optical rotation: []20D = +105 (c 0.5, CHCl3); litii: []20D = +101,9 (c 0.5,
CHCl3). FTIR (film): 3255, 2950, 2854, 1452, 738. 1H-NMR (250 MHz, CDCl3) :
1.80-2.00 (m, 3H); 2.24-2.32 (m, 1H); 2.60-2.66 (m, 1H); 2.80-3.15 (m, 4H); 3.30-3.37
(m, 1H); 4.25-4.30 (m, 1H); 7.10 (m, 2H); 7.31 (d, J 7.3 Hz, 1H); 7.43 (d, J 7.0 Hz,
1H); 8.6 (br, 1H). 13C-NMR (62.5 MHz, CDCl3) : 17.8 (CH2); 23.4 (CH2); 29.4 (CH2);
45.9 (CH2); 49.2 (CH2); 56.9 (CH); 107.8 (C0); 110.7 (CH); 118.1 (CH); 119.4 (CH);
121.4 (CH); 127.3 (C0); 135.3 (C0); 135.9 (C0).
Methyl 5-{[2-(1H-indol-3-yl)ethyl]amino}-5-oxopentanoate (6). To a soln. of
tryptamine (0.200 g, 1.25 mmol) in CH2Cl2 (5 mL) was
added a soln. of glutaric anhydride (0.142 g, 1.25 mmol)
HN
O
in CH2Cl2 (0.5 mL). The reaction mixture was let to react
N
H
at rt under magnetic stirring and after 20 min. the solvent
was removed under reduced pressure. The residue was
O
dissolved in methanol (2.0 mL) and thionyl chloride (0.1
mL, 1.4 mmol) and the mixture was stirred 3 h at rt. The
O
Me solvent was removed under reduced pressure and the
crude product was purified by column chromatography on slica gel (hexane/ethyl
acetate 50%) to afford 6 in 96% yield as a white solid (m.p: 102-103 C; lit4: 104-105
C). FTIR (film): 2945, 1733, 1650, 1553, 1435, 1220, 747. 1H-RMN (300 MHz,
CD3OD) : 1.86 (qt., J=7.5 Hz, 2H); 2.19 (t, J=7.2 Hz, 2H); 2.30 (t, J=7.2 Hz, 2H); 2.94
(t, J=7.2 Hz, 2H); 3.48 (q, J=7.5 Hz, 2H); 3.65 (s, 3H); 6.98-7.11 (m, 3H); 7.33 (d,
J=8.1Hz, 1H), 7.56 (d, J= 8.1Hz, 1H). 13C-RMN (75 MHz, CD3OD) : 22.3 (CH2); 26.4
(CH2); 34.0 (CH2); 36.2 (CH2); 41.5 (CH2); 52.2 (CH3); 112.3 (CH); 113.4 (C0); 119.4
(CH); 119,.7 (CH); 122.4 (CH); 123.5 (CH); 128.9 (C0); 138.3 (C0); 175.3 (C0); 1754
(C0). HRMS (ESI): calcd. for [C15H22N5++ H]+: 289.1552; found. 289.1567.

N
H

CO2Me

To a soln. of 6 (0.290 g, 1.0 mmol) in toluene (7 mL)

and acetonitrile (3 mL) was added POCl3 (0.3 mL, 3
mmol) dropwise and the reaction mixture was then
refluxed for 5 h. The reaction mixture was then cooled
to rt and it was concentrated under vacuum. The crude
reaction mixture was dissolved in CH2Cl2 (20 mL),

S4
washed with aq. 1 M NaHCO3 (15 mL). The organic phase was dried over MgSO4 and
evaporated under reduced pressure. 1H RMN (400 MHz, CDCl3) : 2.00-2.05 (2H, m);
2.48 (2H, br t, J = 6.4 Hz); 2.69 (2H, br t, J = 7.9 Hz); 2.87 (2H, t, J = 8,5 Hz); 3.7 (3H,
s); 3.87 (2H, br t, J = 8.5 Hz); 7.13 (1H, dt, J = 8.2 , 0.9 Hz); 7.26 (1H, dt, J = 8.2 , 0.9
Hz); 7.44 (1H, d, J = 8.2 Hz); 7.57 (1H, d, J = 8.2 Hz); 9.9 (1H, s). 13C RMN (100 MHz,
CDCl3) : 19.3 (CH2), 22.0 (CH2), 32.8 (CH2), 34.8 (CH2), 48.0 (CH2), 51.8 (CH3);
112.2 (C0); 116,6 (Co); 119.8 (CH); 120.0 (CH); 124.4 (CH); 125.3 (C0); 128.4 (C0);
136.9 (C0); 160.9 (C0); 174.96 (C0).
1-Methyl-4,9-dihydro-3H--carboline (1a): 1H
RMN (400 MHz, CDCl3) : 2.38 (3H, s); 2.88 (2H,br
N
N
t,
J = 8.4 Hz); 3.89 (2H, dt, J = 8.4 , 1.1 Hz); 7.14
H
Me
(1H, dt, J = 8.1 , 0.7 Hz); 7.26 (1H, dt, J = 8.1 , 0.7
Hz); 7.39 (1H, br d, J = 8.1 Hz); 7.60 (1H, br d, J =
8.1 Hz); 9.38 (1H, br s, NH). 13C RMN (100 MHz,
CDCl3) : 19.5 (CH2); 22.1 (CH3); 48.20 (CH2); 111.9
(CH); 116.3 (C0); 119.9 (CH); 120.2 (CH); 124.3 (CH); 125.4 (C0); 129.1 (C0); 136.4
(C0); 157.8 (C0). HRMS (70 eV): calcd. for C12H12N2 m/z 184.1000; found 184.1007.
1-ethyl-4,9-dihydro-3H--carboline (1b): cream
solid; m.p. 165-167 C; 1H RMN (400 MHz, CDCl3) :
N
N
1.30 (3H t, J = 7.4 Hz); 2.74 (2H q, J = 7.4 Hz); 2.91
H
Et
(2H t, J = 8.4 Hz); 3.89 (2H, t, J = 8.4 Hz); 7.10-7.63
(4H m); 8.81 (br s, 1H). 13C RMN (100 MHz, CDCl3)
: 10.9 (CH3); 19.3 (CH2); 28.4 (CH2); 48.2 (CH2);
111.9 (CH); 116.8 (C0); 120.0 (CH); 120.3 (CH); 124.4
(CH); 125.6 (C0); 128.6 (C0); 136.6 (C0); 161.7 (C0). HRMS (ESI) for [C13H14N2 + H]+:
calcd. 199.1230, found: 199.1222.
1-Isopropyl-4,9-dihydro-3H--carboline (1c): To a
solution of tryptamine (0.191 g, 1.19 mmol) and
N
propenoic acid (0.136 g, 1.19 mmol) in CH2Cl2 (12.0
N
H
mL) at 0 C were added DCC (0.177 g, 1.31 mmol)
and DMAP (0.251 g, 1.31 mmol). The reaction mixture
was stirred at room temperature for 10 h, then washed
with 5% aqueous HCl (3 x 15.0 mL), 5% aqueous NaHCO3 (20.0 mL), H2O (20.0 mL),
brine (20.0 mL), and dried (Na2SO4). The solvents were removed and the resulting
amide was reacted directly without purification with POCl3 (242 L) in dry benzene
(9.25 mL) and the mmixture was heated to reflux for 2 h, cooled to room temperature,
and then concentrated. The resulting orange viscous oil was purified by chromatography
(CHCl3/MeOH, 10%) to afford a cream solid in 86% yield, which was characterized as
the imine. M.p. 163-166 C. 1H NMR (400 MHz, CDCl3), : 1.28 (br s, 3H); 1.31 (br s,
3H); 2.85 (t, J 8.3 Hz, 2H); 3.02 (m, 1H); 3.88 (t, J 8.3 Hz, 2H); 7.13-7.62 (m, 4H); 8.54
(br, 1H). 13C NMR (100 MHz, CDCl3), : 19.3 (CH2); 20.3 (2x CH3); 28.7 (CH2); 33.2
(CH); 48.1 (CH2); 111.8 (CH); 117.2 (C0); 119.9 (CH); 120.2 (CH); 124.4 (CH); 125.6
(C0); 128.2 (C0); 136.5 (C0); 165.1 (C0). FT-IR (KBr film, cm-1): 3438, 1621, 1601,
1506, 750. HRMS (70 eV): C14H17N2 m/z 213.1386, found: 213.1375.

S5

1-Phenyl-4,9-dihydro-3H--carboline (1e): 1H NMR

(400 MHz, d6-DMSO), : 2.88 (t, J = 7.8 Hz, 2H); 3.90
N
(t, J = 7.8 Hz, 2H); 7.07-7.10 (m, 1H); 7.17-7.21 (m,
N
H
1H); 7.40-7.65 (m, 5H); 7.73-7.78 (m, 2H); 11.00 (br s,
Ph
1H). HRMS (70 eV): C17H14N2 m/z 246.1157, found:
246.1150. The spectrometric data is in accordance with
reference Uematsu, N.; Fujii, A.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am. Chem.
Soc. 1996, 118, 4916-4917.
(R)-1-Methyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole (2a):
NH []D +51 (c = 1.0, MeOH), (lit. (R)-isomer, []D +53.5 (c = 2.08,
N
EtOH), N. Uematsu, A. Fujii, S. Hashiguchi, T. Ikariya and R.
H
Me
Noyori, J. Am. Chem. Soc., 1996, 118, 4916-4917), 90% ee by
HPLC analysis (Chiralcel OD, hexane/2-propanol/diethylamine = 80: 20: 0.1, 1.0
mL/min, 254 nm, minor isomer 8.8 min, major isomer 5.9 min). 1H NMR (400 MHz,
CDCl3), : 1.46 (3H, d, J = 6,7 Hz); 1.80 (1H, br s); 2.88-2.83 (2H, m); 3.05 (1H, ddd, J
= 13.1, 9.2, 5.2 Hz); 3.37 (1H, ddd, J = 13.1, 5.2, 3.7 Hz); 4.19 (1H, tq, J =6.7, 2.0 Hz);
7.09 (1H, dt, J = 7.3, 0.9 Hz); 7.15 (1H, dt, J = 7.3, 0.9 Hz); 7.31 (1H, d, J = 7.3 Hz);
7,48 (1H, d, J = 7.3 Hz); .78 (1H, br s). HRMS (EI): calcd. for C14H18N2 214.1466,
found: 214.1458.
H

(R)-1-Ethyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole
(2b):
NH []D +52.0 (c = 1.0, MeOH), (lit. (S)-isomer, []D 62.6
N
(CH3COCH3), C. Gremmen, B. Willemse, M. J. Wanner and G.-J.
H
Et
Koomen, Org. Lett., 2000, 2, 1955-1958), 83% ee by HPLC
analysis (ChiralPack OD, hexane/2-propanol/diethylamine = 80: 20: 0.1, 1.0 mL/min,
254 nm, major isomer 8.9 min, minor isomer 11.0 min). 1H NMR (400 MHz, CDCl3), :
1.10 (t, J = 7.1 Hz, 3H); 1.67-1.75 (m, 1H); 1.85-2.07 (m, 1H); 2.72-2.78 (m, 2H); 3.003.06 (m, 1H); 3.34-3.40 (m, 1H); 4.00-4.04 (m, 1H); 7.06-7.19 (m, 2H); 7.32 (d, J = 7.2
Hz, 1H); 7.49 (d, J = 7.6 Hz, 1H); 7.77 (br s, 1H). The spectrometric data is in
accordance with references Zhang, X.; Jiang W.; Sui Z. J. Org. Chem. 2003, 68, 45234526 and (a) Taylor, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 10558-10559.
(b) Gremmen, C.; Willemse, B.; Wanner, M. J.; Koomen, G.-J. Org. Lett. 2000, 2,
1955-1958.).
H

(R)-1-Isopropyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole (2c):
H
amine as a creamy solid. []D +65 (c 1.0, MeOH), 70% ee by
NH
N
HPLC analysis (ChiralPack OD, hexane/2-propanol/diethylamine =
H
80: 20: 0.1, 0.8 mL/min, 254 nm, major isomer 6.0 min, minor
isomer 8.0 min). 1H NMR (400 MHz, CDCl3), : 0.91 (d, J= 7.2
Hz, 3H); 1.14 (d, J= 7.2 Hz, 3H); 2.16-2.28 (m, 1H); 2.72-2.77 (m, 2H); 2.93-3.03 (m,
1H); 3.42-3.45 (m, 1H); 4.00-4.04 (m, 1H); 7.10-7.15 (m, 2H); 7.31 (dd, J= 1.4, 7.3 Hz,
1H); 7.50 (dd, J= 1.4, 7.3 Hz, 1H); 7.85 (br s, 1H). HRMS (EI): calcd. for C14H18N2
214.1466, found: 214.1458. FT-IR (KBr film, cm-1): 1466, 3471. The spectrometric data
is in accordance with references: (a) Shankaraiah, N.; da Silva, W. A.; Andrade, C. K.
Z.; Santos, L. S. Tetrahedron Lett. 2008, 49, 42894291. (b) Zhang, X.; Jiang W.; Sui
Z. J. Org. Chem. 2003, 68, 4523-4526. (c) Taylor, M. S.; Jacobsen, E. N. J. Am. Chem.

S6
Soc. 2004, 126, 10558-10559. (d) Gremmen, C.; Willemse, B.; Wanner, M. J.; Koomen,
G.-J. Org. Lett. 2000, 2, 1955-1958.).

(R)-1-Phenyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole
(2e):
[]
4.1
(c
=
1.0,
CHCl
),
(lit.
(R)-isomer,
[]
3.9
(c
=
1.03,
D
3
D
NH
N
CHCl
),
N.
Uematsu,
A.
Fujii,
S.
Hashiguchi,
T.
Ikariya and R.
3
H
Ph
Noyori, J. Am. Chem. Soc., 1996, 118, 4916-4917), 90% ee by
HPLC analysis (ChiralPack OD, hexane/2-propanol/diethylamine = 80: 20: 0.1, 1.0
mL/min, 254 nm, minor isomer 15.8 min, major isomer 19.9 min). 1H NMR (400 MHz,
CDCl3), : 2.83-2.95 (m, 2H); 3.07-3.16 (m, 1H); 3.33-3.39 (m, 1H); 5.17 (s, 1H); 7.107.19 (m, 3H); 7.30-7.37 (m, 5H); 7.56-7.60 (m, 1H); 7.66 (br s, 1H). HRMS (EI): calcd.
for C17H16N2 248.1314, found: 248.1320. The spectrometric data is in accordance with
reference Uematsu, N.; Fujii, A.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am. Chem.
Soc. 1996, 118, 4916-4917.
H

2,3,6,7,12,12b-Hexahydroindolo[2,3-a]quinazolin-4(1H)one (3g). Following the general procedure for -CD mediated

H
N
O reduction and imine 1g, the crude mixture was purified by
N
column chromatography on silica gel (CHCl3: MeOH, 9:1 v/v)
H
to afford a 3g as a viscous oil in 80% yield and 90% ee
determined by HPLC analysis (Welk-01 Column, hexane:2-propanol, 85:15,1.0
mL/min, 254 nm, major isomer 4.2 min, minor isomer 5.1 min). []20D +279 (c 1,
CHCl3). FTIR (film): 3260, 2950, 2847, 1616, 1455, 742. 1H-NMR (300 MHz, CDCl3)
: 1.75-1.96 (m, 3H); 2.35-2.62 (m, 3H); 2.74-2.81 (m, 3H); 4.76-4.80 (m, 1H); 5.125.23 (m, 1H); 7.10-7.20 (m, 2H); 7.34 (d, J=8.1 Hz, 1H); 7.50 (d, J=7.2 Hz, 1H); 8.35
(s, br, 1H). 13C-NMR (75 MHz, CDCl3) : 19.3 (CH2); 21.0 (CH2); 29.0 (CH2); 32.4
(CH2); 40.2 (CH2); 54.4 (CH); 109.3 (C0); 110.9 (CH); 118.3 (CH); 119.7 (CH); 122.0
(CH); 126.8 (C0); 133.3 (C0); 136.2 (C0); 169.3 (C0).
Tert-butil
4-oxo-1,3,4,6,7,12b-hexahydroindolo[2,3a]quinazoline-12(2H)-carboxylate (7). Lactam 3g (0.190 g,
H
N
O 0.80 mmol) was dissolved in THF (10 mL) and triethylamine
N
was added (0.30 mL, 2.0 mmol). After stirring 10 min. at rt,
Boc
(Boc)2O (0.270 g, 1.20 mmol) and DMAP (0.025 g, 0.20 mmol)
and the reaction mixture was stirred 4 h at rt. After evaporation of the solvent under
reduced pressure, the crude was successively washed with aq. satd. NH4Cl (2X10 mL),
aq. satd. NaHCO3 (2X10 mL) and brine (10 mL). The crude product was purified by
column chromatography under silica gel (hexanes/ethyl acetate 2:3 v/v) to afford 7
(0.260 g, 1.92 mmol) in 96% yield as a pale brown oil. Specific optical rotation: []D=
+289 (c=1,8, CH2Cl2); lit 12c: []D = +328 (c=2.0, CH2Cl2). FTIR (film): 3050, 1735,
1639. 1H-NMR (300 MHz, CDCl3) : 1.40-1.46 (m, 1H); 1.66 (s, 9H); 1.90-1.95 (m,
2H); 2.38-2.48 (m, 1H); 2.60-2.67 (m, 2H); 2.70-2.81 (m, 2H); 2.82-2.84 (m, 1H); 5.105.17 (m, 2H); 7.22-7.31 (m, 2H); 7.42-7.45 (m, 1H); 8.06-8.08 (m, 1H). 13C-RMN (75
MHz, CDCl3) : 19.3 (CH2); 21.5 (CH2); 28.1 (3XCH3); 30.1 (CH2); 31.9 (CH2); 39.0
(CH2); 56.0 (CH); 84.2 (C0); 115.4 (CH); 118.2 (CH); 122.9 (CH); 124.5 (CH); 128.5
(C0); 135.1 (C0); 136.7 (C0); 150.1 (C0); 169.8 (C0).

S7
Tert-Butyl
(3E)-3-ethylidene-4-oxo-1,3,4,6,7,12b-hexahydroindolo[2,3a]quinazoline-12(2H)-carbolylate (8). To a soln. of diisopropylamine (0.20 mL, 1.35
mmol) in anhydrous THF (1.0 mL) was added n-butyllithium (1.8 M soln in THF, 1.05
mL, 1.35 mmol) at 0 oC and under a nitrogen atmosphere. After
H
15 min., the mixture was cooled to -78 C and a soln. of 7
N
O
N
(0.210 g, 0.62 mmol) in THF (2 mL) was added via canula.
Boc
The reaction mixture was stirred 30 min. at -78C when freshly
distilled acetaldehyde (0.35 mL, 6.3 mmol) was added via
syringe. The reaction mixture was stirred 30 min. at -78C,
followed by stirring 16 h at rt. The reaction was quenched upon addition of satd. Aq.
NH4Cl (10 mL) and the aqueous phase was extracted with ethyl acetate (2X20 mL). The
combined organic phase was dried over MgSO4, the solvent was evaporated under
reduced pressure to afford a viscous yellow oil which was dissolved in CH2Cl2 (3 mL).
Under a nitrogen atmosphere, the soln. was cooled at -40 C and mesyl chloride (80 L,
1.0 mmol) was added Et3N (0.20 mL). After stirring 30 min. at 40 oC, the reaction was
warmed up to rt and stirred 3 h. The solvent was evaporated under reduced pressure
and the residue was dissolved in THF (5 mL) and DBN (0.25 mL, 2.0mmol) was added.
After stirring 16 h at rt, the solvent was removed and the residue was dissolved in
CH2Cl2 (3 mL) and washed with satd. aq. NH4Cl (2X20 mL). The organic phase was
dried with MgSO4, the solvent was removed under reduced pressure and the crude
product was purified by column chromatography on silica gel (hexanes/ethyl acetate
60:40 v/v) to afford 8 as a pale brown oil (0.152 g, 0,41), in 67% yield. Specific optical
rotation: []20D = +136 (c=2, CH2Cl2); lit12c: []D = 140.4 (c=2.0, CH2Cl2) . FTIR
(film): 1738, 1598. 1H-NMR (300 MHz, CDCl3) : 1.45-1.51 (m, 1H); 1.68 (s, 9H);
1.75 (d, J=8.0, 3H); 2.38-2.48 (m, 1H); 2.56-2.63 (m, 1H); 2.69-2.90 (m, 4H); 5.11-5.21
(m, 2H); 6.97-7.03 (m, 1H); 7.21-7.31 (m, 2H); 7.42-7.44 (m, 1H); 8.03-8.06 (m, 1H).
13
C-NMR (75 MHz, CDCl3) : 13.6 (CH3); 21.5 (CH2); 23.3 (CH2); 28.2 (3XCH3); 30.2
(CH2); 39.0 (CH2); 55.1 (CH); 84.2 (C0); 115.5 (CH); 118.1 (CH); 118.2 (CH); 122.9
(CH); 124.5 (CH); 128.5 (C0); 129.2 (C0); 134.2 (C0); 134.9 (C0); 136,6 (C0); 150,1
(C0); 164,8 (C0).

(3E)3-ethylidene-2,3,6,7,12b-hexahydroindolo[2,3a]quinolizin-4(1H)-one.
To a soln. of 8 (0.075 g, 0.20 mmol)
N
O
N
in aq. MeOH (5 mL, 3:1 v/v was added K2CO3 (0.276 g, 2.0
H
mmol) and the mixture was refluxed for 12 h. The reaction
mixture was evaporated under reduced pressure CH2Cl2 (15
mL) was added. The organic phase was washed with brine
(2X10 mL), dried over MgSO4 and the residue was purified by column chromatography
on silica gel (ethyl acetate) to afford (0.057 g, 0.18 mmol) in 93% yield as a yellow
solid. M.p. 199-201 C (lit 12c= 198-202 C). Specific optical rotation: []20D +80 (c 1,
CH2Cl2); lit12c: []D = 77.2 (c=1.0, CH2Cl2). FTIR (film): 3320, 1746. 1H-NMR (300
MHz, CDCl3) : 1.72-1.82 (m, 1H); 1.77 (dd, J=8 e 4.0 Hz, 3H); 2.31-2.41 (m, 1H);
2.50-2.58 (m, 1H); 2.77-2.97 (m, 4H); 4.81-4.84 (m, 1H); 5.18-5.25 (m, 2H); 7.19 (m,
2H); 7.31-7.34 (m, 1H); 7.49-7.51 (m, 1H); 8.57 (m, 1H). 13C-NMR (75 MHz, CDCl3)
: 13.7 (CH3); 21.0 (CH2); 22.6 (CH2); 28.9 (CH2); 40.6 (CH2); 53.9 (CH); 109.3 (CH);
111.0 (CH); 118.3 (C0); 119.6 (CH); 122.0 (CH); 126.7 (CH); 129.2 (C0); 133.3 (C0);
134.1 (CH); 136.3 (C0); 164.7 (C0).
H

S8
(+)-Deplancheine 9. A flame dried round-bottomed flask was
charged
with AlCl3 (0.114 g, 0.85 mmol) and THF (3.0 mL)
H
N
under nitrogen atmosphere. The mixture was cooled at 0 oC and a
N
H
2,4M THF soln. of LiAlH4 (1.25 mL, 3.0 mmol) was added. After
stirring 10 min. at 0 oC, a soln. of lactam (0.400 g, 1.50 mmol) in
THF (3.0 mL) was added via canula. The reaction mixture was
stirred 30 min. at rt, quenched by the addition of satd. aq. NH4Cl (0.1 mL) and poured
into satd. aq. NaHCO3 (20 mL). After extraction with ethyl acetate (2X15 mL), the
organic phase was washed with brine (2X15 mL) and dried with MgSO4. The crude
product was purified through a pad of silica gel (hexane/ethyl acetate 40%) to afford
(+)-deplancheine 5 (0.363 g, 1.44 mmol) in 96% yield as yellow solid (139-140 C; lit
12c
= 139,5-140,5 C). Specific optical rotation: []20D +54 (c 1, CHCl3); lit 12c: []D =
+52 (c 1, CHCl3). FTIR (film,): 3438, 3035. 1H-NMR (300 MHz, CDCl3) : 1.52-1.61
(m, 1H); 1.66 (d, J= 7.2 Hz, 3H); 1.97-2.02 (m, 1H); 2.14-2.19 (m, 1H); 2.62-2.73 (m,
2H); 2.81-2.84 (m, 1H); 3.00-3.11 (m, 3H); 3.30-3.35 (m, 1H); 3.39-3.41 (m, 1H); 5.48
(q, J=7.5 Hz, 1H); 7.08-7.17 (m, 2H); 7.32-7.35 (m, 1H); 7.47-7.50 (m, 1H); 7.92 (s, br,
1H). 13C-NMR (75 MHz, CDCl3) : 12.8 (CH3); 21.7 (CH2); 26.0 (CH2); 30.5 (CH2);
53.0 (CH2); 60.1 (CH); 63.5 (CH2); 108.3 (C0); 110.6 (CH); 118.1 (CH); 119.3 (2XCH);
121.3 (CH); 127.5 (C0); 134.1 (C0); 134.8 (C0); 136.1 (C0).
1

Agaton, F. S., Lagoutte, D., Poupon, E., Roblot, F., Fournet, A., Gantier, J. C. Hocquemiller, R. J. Nat.
Prod. 2005, 68, 1581.
2
Raheem, I. T., Thiara, P. S., Peterson, E. A., Jacobsen, E. N. J. Am. Chem. Soc. 2007, 129, 13404.
3
Allin, S. M., Gaskell, S. N., Elsegood, M. R. J., Martin, W. P. Tetrahedron Lett. 2007, 5669.
4
Itagaki, M., Soejima, H., Ishii, K., Sugiyama, T., Hayashi, Y., Plant and Soil, 2003, 67.